Bleeding during any surgical operation is a major concern. It delays surgical procedure and prolongs operation time. Significant bleeding also obstructs a surgeon's view of the surgical field. Blood transfusions or the use of blood salvage devices maybe required to compensate for blood lost during and after surgery.
It is routine to tie off large bleeding vessels, press bleeding crevices with direct pressure, use electrocautery, or block punctures with sutures. These methods are moderately successful. More recently, new methods and compositions have been devised to stop bleeding. These include matrices derived from collagen, collagen-derived materials such as Angio-Seal® (Kensey Nash Corporation) and VasoSeal® (Datascope, Inc.); Flowseal™ (Fusion Medical) and Co Stasis™ (Cohesion Tech., Inc); an the combination of thrombin with collagen or fibrinogen.
Collagen is a major structural protein in the human body. Through interaction of peptide sequences comprising the three amino acids, Arg-Gly-Asp (RDG) in the triplex polypeptide fibers of collagen with surface receptors on platelet membranes, collagen-based hemostatic reagents can activate platelets and contribute to fibrin clot formation.
Polyethylene glycol (PEG)-derived matrices, such as functionally active PEG including Focal seal™ (Focal, Inc.) are designed to form a three-dimensional hydrogel at the bleeding site, which prevents fluid loss and seals punctures. Both collagen and PEG based matrices demonstrated effective in situations of diffusion bleeding.
Thrombin triggers a cascading set of chemical reactions leading to blood clot formation. However, the use of thrombin alone is of limited efficacy in hemostasis, primarily due to a lack of a framework to which a clot can adhere. Thus, a combination of thrombin with collagen matrices can accelerate the intrinsic clotting mechanism by significantly concentrating coagulation factors at the bleeding site, thereby increasing efficacy at controlling aggressive bleeding. Examples of such products are Proceed™ (Fusion Medical Technology) and Gelfoam™ (Pharmacia and Upjohn). However, to provide desirable coagulation activity, these require mixing of thrombin with the matrix immediately prior to use in the operating room.
Carboxymethylcellulose (CMC) is a water soluble, biocompatible and bioresorbable semi-synthesized polysaccharide. The safety of commercially available CMC having high purity has been identified and approved by the Food and Drug Administration (FDA) for incorporation into many products. CMC is able to react with various polymers by way of electrostatic interaction, ionic cross-linking, hydrogen bonding, Van der Waals interactions, and physical interpenetration. Because of its safety, convenience and diversity of physico-chemical properties, CMC has demonstrated wide applications in the pharmaceutical, food and cosmetic industries.
CMC is in a larger group of polymers termed “carboxypolysaccharides” (CPS), which include, but are not limited to alginate, hyaluronic acid, carboxyethylcellulose, chitin, and the like. CPS are used in the manufacture of compositions useful for drug delivery and decreasing surgical adhesions. Schwartz (U.S. Pat. No. 5,906,997), discloses compositions and methods for decreasing post surgical adhesions using films of CPS and poly(ethylene oxide) (“PEO”). Schwartz (U.S. Pat. No. 6,017,301) discloses hydrogels of CPS and PEO, their methods of manufacture and use for decreasing adhesion formation. Schwartz (U.S. Pat. No. 6,034,140) discloses association complexes of CPS and PEO and their use in decreasing adhesions. Schwartz (U.S. Pat. No. 6,133,325) discloses anti adhesion membranes made of association complexes of CPS and PEO.
Miller (U.S. Pat. No. 6,174,999) describes methods of preparing water insoluble derivatives of polyanionic polysaccharides, which require one or more polysaccharides, a nucleophile, and an activating agent to crosslink the polysaccharide to itself and the nucleophile to the polysaccharide. The reaction is performed in the presence of hyaluronate or carboxymethyl cellulose (CMC), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (“EDC”), and a nucleophile. This patent does not describe or suggest a primary amine-derivatized polyanionic polymer as a water-soluble product, nor a diamine derivatized polysaccharide. The methods described result in water insoluble forms, because all of the components are mixed together at the same time. Thus, the disclosed compositions would not trap polyethylene oxides (PEO).
Bums (U.S. Pat. No. 6,030,958) describes crosslinking a polysaccharide, and U.S. Pat. No. 5,527,893 describes incorporating an acyl urea derivative of hyaluronic acid (HA).
Goldberg et al (U.S. Pat. No. 6,010,692) describes methods for decreasing surgical adhesions, by which tissue surfaces and surgical articles involved in the surgery are coated with hydrophilic solutions containing hyaluronic acid before the operation.
Bums (U.S. Pat. No. 5,585,361) describes methods for reducing or inhibiting platelet aggregation and adhesion by administering pharmaceutical composition containing hyaluronic acid.
Cook (U.S. Pat. Nos. 6,172,208 and 6,017,895) describe conjugation of saccharides with an oligonucleotide.
Greenawalt (U.S. Pat. No. 6,056,970) describes a hemostatic composition consisting of a bioabsorbable polymer and a hemostatic compound which is prepared in a nonaqueous solvent.
Liu (U.S. Pat. Nos. 5,972,385 and 5,866,165) disclose methods of crosslinking polysaccharides by oxidizing them to aldehydes and reacting them with proteins.
Berg (U.S. Pat. Nos. 5,470,911, 5,476,666 and 5,510,418) describes methods for crosslinking glycosaminoglycans with activated hydrophilic polymers. These patents also described crosslinking collagen to derivatized hyaluronic acid using activated hydrophilic polymers.
Liu (U.S. Pat. No. 6,096,344) described polymeric polysaccharides ionically crosslinked into spheres for drug delivery.